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Elimination of Neurons from the Lateral Geniculate Nucleus of Rhesus Monkeys during Development

Robert W. Williams and Pasko Rakic
Section of Neuroanatomy, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06511

The Journal of Comparative Neurology 272:424–436 (1988)

Authors Notes to the reader: This is a revised version of a paper published in The Journal of Comparative Neurology in 1988. Modifications are delimited by brackets [...].

Enlarging images: Thumbnail versions of all figures are embedded in the paper. A better image—usually under 100K—will download into a separate window if you click on the thumbnail image. If you have a large enough monitor, drag this second figures window beside the text window. Finally, high-resolution images—usually under 1 MB—that almost match the quality of the original prints can be downloaded by selecting the text at the bottom of each legend. These image files can be viewed with Adobe Photoshop, NIH Image, or equivalent.

Revised HTML edition ( copyright © 1998 by Robert W. Williams.



Table of Contents


The timing, magnitude, and spatial distribution of neuron elimination was studied in the dorsal lateral geniculate nucleus of 54 rhesus monkeys (Macaca mulatta) ranging in age from the 48th day of gestation to maturity. Normal and degenerating cells were counted in Nissl-stained sections using video-enhanced differential inference contrast optics and video-overlay microscopy. Before embryonic day 48 (E48), the geniculate nucleus contains 2,200,000 ± 100,000 neurons. Eight-hundred thousand of these neurons are eliminated over a 50-day period spanning the middle third of gestation. Neurons are lost at an average rate of 300 an hour between E48 and E60, and at an average rate of 800 an hour between E60 and E100. Very few neurons are lost after E100, and as early as E105, the population has fallen to the adult average of 1,430,000 ± 90,000. Degenerating neurons are far more common in the magnocellular part of the nucleus than in the parvocellular part. In 19 of 27 cases, the number of neurons is greater on the right than on the left side. The right-left asymmetry averages 8.5% and is significant (chi-square = 17.7, p <0.02).

The elimination of neurons in the nucleus begins before the depletion of retinal axons, and this raises the possibility that the number of geniculate neurons determines the final size of the retinal ganglion cell population rather than vice versa. The period of cell death precedes the emergence of cell layers in the geniculate, the establishment of geniculocortical connections, and the formation of ocular dominance columns.

[Key words:neuron death, dorsal lateral geniculate nucleus, rhesus monkey, primate development]



Little is known about the onset, duration, magnitude, or spatial distribution of neuron elimination in the vertebrate visual system. The analysis of naturally occurring neuron loss has been difficult because embryonic neurons are small and are packed together so tightly, and because the boundaries of visual centers are indistinct at early developmental stages. In this study we have taken advantage of video-enhanced differential interference contrast optics (DIC) and video-overlay microscopy to overcome some of these problems, and using these methods we have been able to estimate the key parameters of neuron elimination in the dorsal lateral geniculate nucleus of a primate—the rhesus monkey, Macaca mulatta—from early in prenatal life through to maturity.

The simplicity of the retino-geniculo-cortical pathway of macaques and its similarity to that of humans makes it an excellent system in which to study interactions that control numbers of neurons in different parts of the visual system (Rakic and Williams, 1986; Williams and Herrup, 1988). More than 90% of all retinal ganglion cells in macaques project only to the lateral geniculate nucleus and more than 90% of all geniculate neurons project only to primary visual cortex (Perry et al, 1984; Norden and Kaas, 1978; Hamori et al., 1983; Pasik et al., 1986). Furthermore, we know when neurons are generated and when synaptic contacts are established in the visual system of macaques (Rakic, 1974, 1976, 1977ab; LaVail et al., 1983; Shatz and Rakic, 1981; Hendrickson and Rakic, 1977; Kostovic and Rakic, 1984; Nishimura and Rakic, 1985, 1987; Bourgeois and Rakic, 1983). Consequently, changes in the population of neurons in the geniculate nucleus can now be studied profitably with respect to other cellular events in development—for instance, the innervation of the nucleus by retinal and cortical axons, the elimination of retinal ganglion cells and their axons, the lamination of the nucleus, the innervation of primary visual cortex by geniculate fibers, and the development of ocular dominance columns.



This study is based on an analysis of 54 animals ranging in age from E48 to maturity. Normal monkey fetuses of known gestational age were delivered by cesarian section and while anesthetized with Halothane were perfused through the heart with saline and mixed aldehydes (Rakic, 1972). Postnatal monkeys were anesthetized with sodium pentobarbital and were perfused with either formalin or mixed aldehydes.

Brains were sectioned serially in the coronal (n = 50) or horizontal (n = 4) planes, and a minimum of every tenth section was mounted and stained with cresyl violet or Toluidine blue. Much of the material was taken from a pre-existing rhesus macaque brain collection, and because several embedding and cutting protocols had been used to prepare this material, it was necessary to ensure that the estimates did not depend on large or small differences in processing. Four control cases (E61, E66, E128, and P0) were prepared in which right and left sides of the brain were embedded in different media (celloidin vs. paraffin, or celloidin vs. a 30% solution of sucrose) and cut at different thicknesses (20 and 35 µm). Right versus left differences for this group averaged 11.4% compared to an average difference of 8.9% for all other material. This difference is not significant. In addition to these control cases, 11 prenatal brains were embedded only in celloidin and sectioned at 35 µm (Yakovlev, 1970), while an additional 11 brains were cut frozen at 30 or 40 µm. Two neonatal brains (P0 and P11) were were cut in paraffin at 20 µ;m whereas one other neonatal brain (P15) was cut frozen at 40 µm. All other postnatal brains (n = 18) were embedded in celloidin and sectioned at 35 µm. Finally, 7 of the youngest cases (E48, 50, 54, 55, 59, 60, and 70) were embedded in polyester wax and sectioned at 8 µm (Rakic, 1977). These latter cases were used only to estimate the fraction of degenerating cells in the thalamus (see below).

Immunocytochemistry. To corroborate criteria used to distinguish neurons from glial cells (see Recognition of neurons), we examined sections of the thalamus immunoreacted with antibodies directed against glial fibrillary acid protein (GFAP) at three ages—E72, E78, and E90. Methods and controls used to prepare tissue are described in papers by Levitt and Rakic (1980) and Levitt et al. (1983). Tissue was cut on a Vibratome at 60 µm, and sections were incubated for 15 h in a 1:500 dilution of rabbit antiserum and 5% normal goat serum. Avidin-biotin conjugate and diaminobenzidine were subsequently used to localize GFAP.

Estimation of cell numbers

Direct estimates of neuron number in the geniculate nucleus were obtained for 47 rhesus monkeys. In 27 of these cases, estimates were obtained from both sides, and the means of right and left sides were used in all subsequent calculations. The accuracy of the estimates depends crucially on five factors:

  1. the recognition of neurons
  2. the accuracy of counting
  3. the precision of estimates of geniculate volume
  4. the sampling procedure
  5. the correction factors used to compensate for the split cell effect (see Konigsmark, 1970).

The procedures and problems associated with each of these factors are considered below.


Recognition of neurons. Counts were performed at a final magnification of x2500 using a x100 oil immersion objective and video-enhanced DIC optics (Inoue, 1986). The following morphological criteria were used to distinguish neurons from glial cells, endothelial cells, and pericytes:

  1. Nuclei of neurons have prominent nucleoli and smooth nucleoplasm, whereas glial cells and pericytes usually have small, dark nucleoli, scattered clumps of heterochromatin, and rough nucleoplasm (Ling et al., 1973)


  2. Neurons contain more abundant and more granular Nissl substance than other cell types.


  3. Cell bodies and nuclei of neurons typically have cross-sectional areas two to three times larger than those of glial cells even at early developmental stages. Although local circuit neurons are only slightly larger than glial cells, they have prominent nucleoli that set them apart from glial cells.


  4. Nuclei of neurons are round or oval whereas those of glial cells are irregularly shaped, often with sharp indentations. Pericytes and endothelial cells are oblong or crescent-shaped, have densely stained chromatin, and are associated with capillaries. Between E61 and E78 the distinction between neurons and other cell types, although less obvious than in late fetal and neonatal material, could be made accurately in the majority of cases (Figs 1, 2).

We consider problems associated with the distinction of cells during this period, and how these problems may affect the interpretation, in the Results section.

Accuracy of counting. The number of neurons in a single counting frame ranged from 5 to 250. Neurons were counted if they were completely within the margins of the frame or if they intersected only its upper or right sides (Gundersen, 1977). Even at a magnification of 2500, it is possible to miss 10% of the cells, particularly when the packing density is high. To improve the accuracy of counting we have used video-enhanced DIC optics in combination with a video-overlay system. A camera (Hamamatsu C2400) was mounted on the microscope, and the field of cells was viewed on a video monitor (Sony PVM-1271Q). The outlines of each cell (nucleus or nucleolus) were traced at x2500 on the screen of the monitor using a digitizing tablet as an input device. Because cells were marked and measured on the monitor, errors of omission and commission were easily detected and corrected.

Estimation of the total volume. Outlines of the geniculate nucleus were drawn and measured at evenly spaced intervals through the entire nucleus. The length of the nucleus orthogonal to the cutting plane was estimated by multiplying the mean section thickness by the number of sections, and the total volume was calculated by multiplying the average area by the length.

Figure 1
Figure 1: Photomicrographs of the posterior thalamus on the 66th day of gestation. (A) Low magnification view of a coronal section cut through the thalamus. The dorsal lateral geniculate nucleus is clearly separated from adjoining thalamic nuclei at this age (two small arrows) . (B) Appearance of cells in the geniculate nucleus close to the pial margin (see the location of the small white spot in A viewed with DIC optics at approximately the same magnification as used to count. The depth of focus of this view is less than 0.5 µm. Because the section is 35 µm thick, many more neurons were counted per field than can be seen at any one plane of focus. For this reason the video-overlay system (see Material and Methods) was necessary to keep track of counted and uncounted cells.

Sampling procedures. The density of neurons in the geniculate nucleus varies with position. Neurons are scattered more widely in the interlaminar zones than within the cell layers, and cell densities are lower in magnocellular layers than in parvocellular layers even as early as E86. In contrast, there are only negligible regional differences within layers. However, because the overall laminar makeup of the nucleus—that is, the combination and spacing of layers present in any given section—differs from front to back or from top to bottom (Kaas et al., 1978), and because of differences in the distribution of fibers of passage, there are rostrocaudal gradients in cell packing density. For instance, the mean difference along the rostrocaudal axis varies from 15 to 30% in postnatal animals (Kupfer et al., 1967).

To get a balanced sample, all layers were examined in a series of fields extending from the ventral-most layer (layer 1 or the superficial layer S) through to layer 6 at three or more levels. The difference between our standard sampling method (one translaminar probe per section, typically three to six sections examined per nucleus) and a more extensive, uniform sampling procedure (up to 10 probes per section, 8 to 10 sections examined per nucleus) was under 10%.

Correction factor. The counts were corrected using Floedrus' equation

Ncor = Nraw x [t/(t + S - 2b)]

Figure 2


Figure 2. Plot of neuron number from E61 to maturity in the dorsal lateral geniculate nucleus. Each point represents a single animal, and in those cases in which both nuclei were counted, the average value is plotted. As early as E105, the neuron population is in the middle of the adult range. Adult values have been spread slightly in the horizontal axis. Compare this figure with Fig. 8, which shows how the changes in neuron number correspond to other phases of visual system development in the rhesus monkey.

(summarized in Konigsmark, 1970; his equations 3 and 4), where Ncor and Nraw are the corrected and raw number of neurons; t is the thickness of the section; S is the mean diameter of the population of nuclei in the axis perpendicular to the plane of the section; and b is an estimate of the size of the lost polar cap. In celloidin material, t—the thickness of individual sections—was measured at a resolution of 0.5 µm at several sites along each probe. In frozen and paraffin material, the microtome setting was used as an estimate of t. b—a value used to estimate the size below which the criterion structure can not be seen—was set at 1 µm (see Konigsmark, 1970).

The standard deviation of the set of counts per probe was used to compute a 95% confidence interval for each estimate. Data were entered into a computer (Macintosh II) and all calculations and corrections were performed automatically using a spreadsheet program (Microsoft Excel).

Counting and plotting degenerating cells. In Nissl-stained tissue, degenerating cells, appear as dark, uniformly stained blobs (Fig. 6). They look like ink spots, and are often surrounded by pale halos. Their appearance does not depend to any significant degree on embedding method or fixation quality. For purposes of counting, a site of cell degeneration was defined as a region with a diameter of 10 to 15 µm containing between one and ten darkly stained blobs each with an diameter between 0.5 and 4.0 µm. We counted and plotted these pyknotic sites in a minimum of eight sections through the geniculate nucleus using a 63X oil immersion objective. After making corrections for differences in the areas of these sections, we calculated the incidence of cell degeneration for the entire nucleus. The issue of the identity of degenerating cells is taken up in the next section.

Figures 3 and 4
Figure 3. Examples of glial cells and neurons at E78 to illustrate the criteria used for classification of cells. A. Glial cells in the optic tract just below the geniculate nucleus photographed in 35 micron-thick celloidin tissue with DIC optics on the 78th day of gestation. As described in Material and Methods, glial cells are smaller and have less distinct nucleoli than do neurons. B. Neurons and several glial cells (small arrows) within the geniculate nucleus. Scale bar represents 10 µm.
Figure 4. Anti-glial fibrillary acid protein antibody (GFAP) labeling of the dorsal thalamus at E78; DIC optics. (A) Immunoreactivity within the geniculate nucleus is light. Few processes and even fewer cell bodies are labeled. In this micrograph only a single labeled astrocyte is visible (small arrow). (B). In contrast, the immunoreactivity is intense in other parts of the thalamus—in this case in a region just a few hundred micron above the geniculate nucleus. Many astrocytes are GFAP-positive. Scale bar represents 250 µm.


Rise and fall of neuron number. All geniculate neurons are generated before E45 and have completed their migration by E50 (Rakic, 1977a). As early as the E60s, the boundaries of the geniculate nucleus can be recognized (Fig. 1A) and consequently, the total number of cells can be estimated accurately. At this age, the prospective magnocellular layers are located close to the ventral and lateral surface of the nucleus (Fig. 1B); the parvocellular layers are more dorsal and medial (Rakic, 1977a). With the exception of a few small, darkly stained pericytes, endothelial cells, and a thin layer of subpial glia, cells are uniform in size and appearance (Fig 1B). Direct estimates of neuron number were obtained from a total of 72 nuclei from 45 animals between the ages of E61 and maturity. We have been able to obtain estimates of neuron number in younger animals only by indirect methods (see Analysis of degenerating cells).

At E61 and E66 there are between 2,000,000 and 2,200,000 neurons in the nucleus (Fig. 2). The number of glial cells, pericytes, and endothelial cells at this stage is low (see below), and consequently these figures do not significantly over- or underestimate the total neuron population. Comparisons of the cytological characteristics of glial cells in the optic tract (Fig. 3A) with the major class of cells in the nucleus (Fig. 3B) reveal clear differences between neurons and glia. The nuclei of cells in the geniculate considered to be neurons are ovoid and contain up to 6 distinct nucleoli. In contrast, glial cells in the optic tract, and cells suspected to be glial cells in the geniculate nucleus, generally have irregularly shaped nuclei and either have no visible nucleoli or have peripheral nucleoli and heterochromatin typical of astrocytes (Ling et al., 1973). Using these criteria the number of glial cells within the geniculate nucleus from E66 through E78 is estimated to be under 100,000.

A further confirmation of the small number of glial cells in young fetuses comes from the analysis of the tissue reacted with antibodies directed against GFAP (Fig. 4). Examination of the E72, E78, and E90 tissue reveals that few cells carry this glial marker at these ages. Although the ventral and medial diencephalon contains immunolabeled cell bodies and heavily stained radial glial fibers (also see Levitt and Rakic, 1980), there are remarkably few labeled cells or processes in the geniculate nucleus of the same sections. Although the limitations of immunocytochemical methods preclude a detailed quantitative analysis, the fraction of labeled cells appears to be under 5%.

Neuron number in the geniculate nucleus remains well above the adult range as late as the E90s (Fig. 2). For purposes of statistical comparison, we have grouped all fetuses between E61 and E100 together: the average number of neurons in the lateral geniculate in this group of animals is 1,870,000. The 95% confidence interval of this average is ± 90,000 neurons (n=13). The range is greater because of the systematic reduction in neuron number with age and because of the natural variation between individuals.

In the group of animals between E105 and E165, the lateral geniculate contains 1,445,000 ± 60,000 neurons (n=11). During this two-month period there is no evidence of any gradual reduction in neuron number. Likewise, between birth and 30 days the geniculate nucleus contains a similar number of neurons: an average of 1,570,000 ± 104,000 (n=7). Finally, in juveniles and mature adults the average number of neurons is 1,420,000 ± 87,000 (n=10).

As mentioned above the variation in the number of neurons in the nucleus within an age group may be substantial. For instance, at birth estimates range from 1,350,000 to nearly 1,800,000. The average confidence interval of ± 12% suggests that at least part of the variation is inherent in the counting procedure. Nonetheless, true individual differences also appear to be an important source of variation. Increasing the number of probes per nucleus to reduce sampling errors does not appreciably reduce the range of estimates.

Right-left asymmetry. In 19 of 27 animals in which both nuclei were counted, the right side contained more neurons. The probability of obtaining a 19 to 8 distribution by chance is 0.05 (two-tailed binomial probability). The bias for 10 adults was 8 right versus 2 left. The bias for 4 fetuses during the period of neuron loss (E61 to E100) was 3 right versus 1 left. A review of our procedure and the sequence of data collection revealed no likely source of bias (e.g., order of counting left and right sides, etc.). Furthermore, since we did not notice the right-side bias in our set of data until after all 54 of these nuclei had been counted, it is unlikely that the bias was introduced during counting.

The magnitude of the right-left differences was greater than 5% in all but two cases (Fig. 5). The average difference between right and left nuclei, irrespective of whether right or left contained more neurons was approximately 150,000 neurons (8.5%). However, the cumulative right bias for all animals was 3.26% and the standard deviation was 9.12%. If this right/left differences were due to small scale variation around a true mean of zero (see Fig. 5), then it would be expected that observations cluster near the 0% point. The data clearly suggest otherwise. Statistical analysis using the chi-square test for goodness of fit demonstrates that the observations do not belong to a population with a normal distribution and with equal numbers of neurons in each nucleus (c2= 17.7 and p less than .02; tested using classes of half a standard deviation).

Analysis of dying cells

Number of dying cells. To estimate how many neurons are lost before E60, we counted and plotted degenerating cells in and around the geniculate nucleus between E48 and E60. Even as early as E48, the geniculate nucleus can be easily recognized, although its medial border is indistinct. To complement this analysis we also determined the number and distribution of degenerating cells in several of the older fetal tissue for which neuron counts had been obtained. We are confident that at early the majority of dying cells at early stages of development are in fact neurons and not glial cells or pericytes. The sites of necrosis are often large, they are unevenly distributed, and they are most abundant during the period when neuron number is dropping most rapidly. Furthermore, there are very few degenerating cells in the optic tract and optic radiations before E90, suggesting that the rate of glial degeneration in the nucleus is probably low. However, in older fetal material and in neonates, the incidence of cell degeneration in the optic tract and optic radiations is high (see Williams and Rakic, 1985, for a note on the problem of dying glial cells at late stages of development). For this reason we did not undertake any quantitative analysis of necrosis in the geniculate nucleus in animals older than E90.


Figure 5


Figure 5. Right-left asymmetry of neuron number in the geniculate nucleus of 27 animals for which both sides were counted. In 19 animals the right nucleus had more neurons, in the other 8 the left nucleus had more neurons. Binomial and chi-square tests (see Results) reveal that this distribution is significantly different from that expected from sampling a population with a normal distribution and a mean right-left difference of 0%.

The incidence of cell necrosis is highly variable in young fetuses. Three- or four-fold differences are not uncommon between animals that are separated in age by only a few days (Table 1). It is unlikely that this variability is due to to fixation or tissue processing because the number of dying cells on left and right sides were within 35% of each other, even when the sides had been processed differently. Furthermore, we consistently observed concentration of degenerating cells in the same parts of the nucleus in different fetuses. 1 One likely source for this variation may be differences in the time required to clear away degenerating cells. An increase in the clearance time will give rise to an increase in the incidence of degeneration even if the rate of necrosis is constant. While we cannot estimate variation in the clearance time, we can estimate the average clearance time. About 800,000 neurons are eliminated between E60 and E100, or about 800 per hour. If the clearance time were exactly 1 hour we would expect each nucleus to contain 800 necrotic sites. In fact, nuclei typically had half again as many necrotic sites (1200 sites or 1 site per 1,500 normal neurons). Thus, the average clearance time over this 40-day period is probably in the neighborhood of 1.5 hours.

Table 1. Highly Variable Incidence of Cell Degeneration

  Number of degeneration sites
AGE * per 100,000 normal neurons

E48 11.10
E50 4.05
E54 0.83
E55 2.50
E59 0.77
E60 4.00
E61 1.17
E66A right 7.76
E66A left 8.00
E66B 12.20
E68 3.70
E70A 20.00
E70B right 19.80
E70B left 27.00
E72 7.60
E78 16.00
E86A 6.90
E86B 12.50
E87 right 15.40
E87 left 9.10

* A's and B's refer to different animals of the same gestational age.  

The estimate of the number of neurons eliminated before E60 is based on (1) the average incidence of cell degeneration in the anlage of the geniculate nucleus from E48 to E60—about 1 in 4,000, and (2) the average incidence of cell degeneration from E61 to E90—about 1 in 1,500. Since the incidence of dying cells between E48 and E60 is only a third that between E61 and E90, it is likely that only 250 to 300 neurons are lost each hour during the earlier phase of cell loss. Additional cells may be lost even before E48, perhaps while migrating toward the lateral margins of the diencephalon, but it is unlikely that this loss would exceed 6,000 to 8,000 cells per day. Therefore, the cumulative loss of neurons from the end of neurogenesis (ca. E45) to E60 is in the neighborhood of 50,000 to 100,000.

Distribution of degenerating cells

The distribution of pyknotic cells in the geniculate nucleus is remarkably uneven. In the youngest animals—E48 and E61—the majority of dead cells are located within 100 µ;m of the lateral margin of the nucleus. This area consists mainly of the first generated geniculate neurons, many of which are eventually situated in the magnocellular layers (Rakic '77a). The focus of cell death shifts during the E60s: In virtually every specimen examined between the ages of E66 and E80, a substantial majority of the dead cells are situated in the ventromedial sector of the nucleus (Fig. 6B). In several cases, including that illustrated in figure 6, more than 80% of the degenerating cells are restricted to the ventromedial sector, which makes up less than 20% of the nucleus. The incidence of necrosis reaches extremely high levels—1 dead cell among 50 normal neurons—an incidence unequaled anywhere else in the diencephalon except the midline nuclei of the posterior thalamus. In marked contrast, the incidence of dying cells in the much larger dorso-lateral part of the nucleus, the parvocellular moiety, is generally under 1 in 10,000.

In cases examined between E80 and E90 the greatest incidence of necrosis is also found in the ventral part of the nucleus, but during this period the entire medio-lateral margin of the nucleus is involved (Fig. 7). This ventral region is made up of the magnocellular layers and the thin, almost vestigial, S layers. The cumulative incidence of necrosis within the magnocellular sector of the nucleus over the entire period from E48 to E100 is as much as 10-fold higher than the incidence in the parvocellular layers.




Time and magnitude of neuron loss

We have shown that the dorsal lateral geniculate nucleus of fetal rhesus monkeys contains approximately 2,200,000 neurons—800,000 more than adults. The 36% excess is eliminated over a 50-day period that ends more than 2 months before birth. Given the substantial qualitative and quantitative similarity of the visual systems of rhesus monkeys and humans, it is likely that a similar number of neurons are eliminated from the human lateral geniculate nucleus toward the end of the first trimester (see footnote 2).

A comparison with cell loss in mice and hamsters

Neuron number in the geniculate nucleus has been studied previously only in postnatal rodents. In mouse, the population drops from 24,000 at birth to 17,000 at one month (Heumann and Rabinowicz, 1980). An equivalent loss has also been reported in rats (Matthews et al.,'82; Satorre et al., 1986). However, there is no consensus on the rate or exact timing of this loss: Heumann and Rabinowicz report a gradual decline, while Satorre et al. report an initial rise from birth to P10 followed by a rapid decline. To add further complexity, two waves of cell death have been described in another rodent, the hamster, one on the fifth day and one on the eighth day (Sengelaub et al.,'85). The differences in the kinetics of neuron loss in these rapidly developing species has made it difficult to correlate the loss with other events in the development of the rodent visual system. It is interesting, and perhaps significant, that the percentage of neurons lost in rodents and primates is close, despite the fact that the primate geniculate is a much more highly differentiated structure (Balado and Franke, 1937; Dreher et al., 1976; Kaas, et al., 1978, Schiller and Malpeli, 1978; Marrocco et al., 1982). Given the wealth of information on the development of the visual system of the domestic cat (e.g., Chalupa and Williams, 1985; Shatz and Sretavan, 1986; Williams et al., 1986), it would be of considerable interest to determine key parameters of neuron elimination in this species' geniculate nucleus.

Figure 6
Figure 6. Necrotic cells in the dorsal lateral geniculate nucleus at E66. These degenerating cells were located in the ventro-medial part of the nucleus in section 20 of figure 7A.

It is important to avoid making the tacit assumption that dying neurons in the geniculate nucleus are all principal neurons with real or potential projections into the telecephalon. Many dying cells may be local circuit neurons. In the mouse cerebellum, for instance, the number of local circuit neurons (granule cells) is reduced about 30% during the first postnatal month, whereas the number of principal neurons (Purkinje cells) is not reduced at all (Caddy and Biscoe, 1979). In our own work, we have counted the entire neuron population because we could not reliably distinguish between types of neurons. While there are few local circuit neurons in the adult rhesus monkey's geniculate nucleus (Norden and Kaas, 1978; Hamori et al., 1983; Pasik et al., 1986, cf. Montero and Zempel, 1986) this obviously may not be true early in development. One piece of evidence we have that bears on the identity of degenerating cells is their very high frequency in prospective magnocellular layers. In the adult rhesus these layers actually contain twice as many local circuit neurons as parvocellular layers (Pasik et al., 1986)—a pattern opposite what one would predict if a substantial number of dying cells were local circuit neurons. This interesting problem might be addressed directly by performing a quantitative analysis of sections of prenatal geniculate nucleus stained with antibodies directed against GABA (e.g., Shotwell et al., 1986), the transmitter used by local circuit neurons in the mammalian geniculate nucleus.

Quantitative asymmetry of the primate LGN

The average surplus of 150,000 neurons in the right lateral geniculate of 70% of the animals we studied could result from unequal production of neurons in left and right halves of the brain or it could result from unequal loss of neurons in two nuclei. In theory the merits of these alternatives could be tested by studying animals before neurons died and by determining whether the incidence of necrosis is asymmetric. Unfortunately, at his point we do not have enough information to address this problem. One clear implication of the right side bias is that the number of geniculate neurons subserving the left visual hemifield will often be more than 5% greater than the number subserving the right hemifield. Williams and Herrup (1988) have reviewed the relationship between neuron number and function, and they point out that even large differences in neuron number often fail to give rise to detectable behavioral differences. For this reason, it is unlikely that routine tests would reveal any consistent difference. However, if the asymmetry seen in the lateral geniculate nucleus is matched by an equal or even greater asymmetry in primary visual cortex (R.W. Williams, K. Ryder, and P. Rakic, in progress), then there will be more of a basis for studying the possible functional significance of this finding.


Figure 7
Figure 7. Distribution of degenerating cells in coronal sections through the dorsal lateral geniculate nucleus at E66 (7A) and at E87 (7B). At E66 the majority of pyknotic cells are located in the ventro-medial part of the nucleus. This distribution characterized the geniculate nucleus between E60 and E80. At E87 the majority of dying cells are located in the ventral part of the nucleus made up of magnocellular layers 1 and 2. In the caudal-most section of 7B, the magnocellular layers are oriented in the dorsoventral axis on the medial side of the nucleus.

Timing of cell death in the geniculate nucleus and the retina

A major finding of the present study is that neuron death in the geniculate nucleus starts as early as E48, long before there is evidence of any reduction in ganglion cell number (Rakic and Riley, 1983). In fact, at the time neuron loss begins in the geniculate, only half of the population of retinal ganglion cells has yet been generated (LaVail et al., 1983; Rakic and Riley, 1983) and few if any optic axons have grown into the nucleus (Williams and Rakic, 1985). Therefore, neuron elimination in the geniculate nucleus cannot result from cell death in the retina (Fig. 8). Instead the reverse may be true: the number of geniculate neurons may regulate the survival of ganglion cells. A 30% to 40% reduction in the number of geniculate neurons may trigger the 50% to 60% reduction in the number of retinal ganglion cells.

A retrograde pattern of control of neuron number may be most pronounced in the visual system of species, such as Macaca mulatta, in which a very high percentage of retinal ganglion cells project exclusively to the lateral geniculate nucleus (Perry et al., 1984). Experimental studies in fetal and neonatal primates support this idea. Ablations of primary visual cortex before birth or in infancy cause a rapid and near total loss of geniculate neurons, and this loss has swift retrograde effects on retinal ganglion cells: 70% to 80% of these cells die (Weller et al., 1979; Dineen and Hendrickson, 1981; Ogren et al., 1984). The present results and data of Rakic and Riley (1983), indicate that the dependence of retinal ganglion cells on geniculate neurons may develop as early as E80—about a week after the last retinal ganglion cells have been generated (LaVail et al., 1983).


Figure 8


Figure 8. Schematic representation of the timing of major processes in the development of the primary visual pathway in the rhesus monkey based on the results of this study, Rakic (1976, 1977a, 1977b), and Rakic and Riley (1983a). A particularly important observation is that the loss of neurons in the geniculate nucleus (black line) is essentially complete by the time the number of optic axons in the nerve begins to fall (gray line).

The sensitivity of ganglion cells to a reduction in the number of geniculate neurons is not matched by an equal sensitivity of geniculate neurons to a reduction in the number of ganglion cells. Although the removal of one eye early in development causes a 50% drop in the number of retinal axons innervating the geniculate nuclei, there is no evidence for any substantial reduction in the number of geniculate neurons (P. Rakic and R.W. Williams, in progress). The independence of geniculate neurons to a substantial loss of retinal axons may be due to the major projections the nucleus gets from cortex and brainstem.

Neuron death and lamination.

The development of cell layers in the geniculate begins around E85 and is complete by about E110 (Fig. 8). If lamination involved the selective loss of neurons, one would anticipate that neuron loss would continue after E100, and one would anticipate that neuron loss would be as common in parvocellular as in magnocellular parts of the nucleus. Neither of these predictions is correct, and consequently, the formation of laminae is evidently not associated with appreciable neuron death. Lamination is probably caused by the growth and redistribution of cells, dendrites, and fibers.

Neuron death and the formation of retinotopic maps

There is good evidence that the formation of retinal projections involves the selective elimination of ganglion cells that make incorrect connections (McLoon, 1982; Insausti et al., 84; Jeffery, 1984; O'Leary et al., 1986; Jacobs et al., 1984, Rakic, 1981; Rakic and Riley, 1983; Williams et al., 1983; Rakic, 1986). In marked contrast, our results demonstrate that neuron number in the geniculate nucleus is stable during the entire period from E110 to E140 when geniculate axons grow into the cortical layers and establish the geniculocortical projection (Fig. 8). It is evident that this precise retinotopic projection is established without the the benefit of cell loss. Thus at the level of retina and its targets, the refinement of connections appears to be achieved in part by the selective elimination of incorrectly connected subsets of ganglion cells, whereas at the level of the geniculate nucleus and its target, the refinement is achieved without any neuron loss. [Footnote 3.]

Neuron loss and the development of ocular dominance columns

The segregation of ocular dominance stripes in the primary visual cortex of the rhesus monkey begins during the last month of gestation and is complete two months after birth (Rakic '76; Hubel et al., 1977; LeVay et al., 1980). LeVay and Stryker (1978) have illustrated arbors of individual Golgi-impregnated geniculocortical axons in neonatal cat that extend uniformly over territories that in adults would occupy several ocular dominance stripes. On the basis of this finding they concluded that segregation results from "synchronous changes in the arborizations of thousands of overlapping geniculocortical axons." Their result does not rule out an alternative, namely, that the refinement is attributable to the selective elimination of geniculate neurons that make incorrect connections. Because, segregation occurs long after the period of neuron death in the geniculate nucleus, we can now rule out this alternative.

Positional specificity of neuron loss

Degenerating cells in the fetal monkey geniculate nucleus are located principally in ventral and ventro-medial parts of the nucleus. This zone overlaps extensively with the prospective magnocellular layers. In contrast, cell loss is light in the dorsal part of nucleus that gives rise to the four parvocellular layers. There are several possible interpretation of this finding:

  • Ratios between the two major types of projection neurons in the geniculate nucleus (magnocellular Y-type and parvocellular X-type) may be adjusted by the elimination of young magnocellular neurons. An effective way to adjust ratios would be to eliminate members of the less numerous cell class—in this case the magnocellular Y-type neurons.
  • The spatial segregation of the two major neuron classes may involve the selective elimination of magnocellular Y-type cells located in the parvocellular layers and of parvocellular X-type neurons located in the magnocellular layers. However, it is important to note that the segregation of cell types in the adult monkey is far from perfect. About 1 in 50 neurons recorded in the parvocellular layers is Y-type (Marrocco, 1982) and according to Shapley et al. (1981) as many as 3 out of 4 cells in the magnocellular layers are X-type.
  • The focus of necrosis in the ventral region may reflect the elimination of a transient population of S-type neurons. This idea is based on a suggestion of Kaas and colleagues (1978) that the ventrally situated S layers are regressive in several primate species, including rhesus macaques.
  • The ventro-medial bias in the incidence of cell degeneration suggests that more neurons may die in the region that represents the periphery of the visual field (eccentricities greater than 15 degrees) than in the dorsocaudal region that represents the center of the visual field (Malpeli and Baker, 1975). Sengelaub et al. (1985) have previously reported that the loss of geniculate cells in hamsters in greatest in a region that represents the periphery of the contralateral visual hemifield.

Experimental and comparative approaches would be effective in testing the validity of these ideas.

Neuron death and the cortical target

The dependence of young neurons on their target cells has been demonstrated in several systems (reviewed by Hamburger and Oppenheim, 1982; Williams and Herrup, 1988). For instance, in the retinogeniculate system, the reduction in neuron number in the central target—the geniculate nucleus—may initiate a reduction in the number of neurons in retina. This notion that the survival of retinal ganglion cells depends on the number of geniculate neurons stands in contrast to the somatosensory system, in which there is reason to believe that the survival of the central neurons depends on the status of the periphery (Johnson et al., 1972; Rowe, 1982; van der Loos and Welker, 1985).

Is the loss of geniculate neurons also regulated by interactions with target cells? The principal targets of these thalamic neurons are cells in striate cortex—stellate cells of layer IV, ascending dendrites of layer V and VI pyramidal cells, and descending dendrites of layer III pyramidal cells (Garey and Powell, 1971; Peters, et al., 1979; White, 1979). At the time the loss begins (ca. E48), only those cortical neurons destined for the deep layers V and VI are being generated, whereas the stellate cells of layer IVC and the pyramidal cells of layer III are not generated until after E66 (Rakic, 1974). All these young neurons migrate up into the cortical plate after passing through a plexus of geniculate axons situated in the optic radiations and the subplate (Rakic, 1977b). While contacts between geniculate axons and migrating neurons during this period have not been demonstrated yet (Kostovic and Rakic, 1980; Chun et al., 1987), it is nonetheless possible that interactions between the two modulate the severity of neuron loss in the thalamus; and it may be more than just coincidental that the period of heaviest neuron death occurs when layer IV neurons migrate through the plexus of geniculate axons. Interactions between thalamic axons and young cortical neurons certainly exercise strong control over the size and number of neurons in the visual cortex of primates. We have been able to demonstrate that reducing the number of geniculate neurons causes a matched reduction in the number of neurons in visual cortex (Rakic and Williams, 1986). Work in progress suggests that the critical period for this type of manipulation extends from E60 to E100, almost precisely the period during which cortical neurons are migrating through the subplate and the plexus of geniculate axons.



We thank Kathryn Ryder for helping us perform the analysis; Dr. Patricia Goldman-Rakic for providing us with tissue; and Dr. Prabhat Sehgal for surgery and acquisition of fetuses of known gestational age. Supported by grant EY 02593 to PR. The fetuses were obtained through the primate breeding colony (Yale University School of Medicine) supported in part by program project NS 22807, and from the New England Regional Primate Research Center, Southboro, MA.


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Footnote 1. High variability (up to 10-fold) in the index of necrosis has been noted previously by Prestige (1970, his figure 2B) in the spinal cord of Xenopus larvae, even though absolute neuron numbers in the same animals show very little variation.


Footnote 2. Both humans and rhesus macaques have 1.2 to 1.5 million retinal ganglion cells and about 1.0 to 1.5 million geniculate neurons (Chacko, 1948; Chow et al., 1950; Sullivan et al., 1958). Developmental changes in the number of retinal ganglion cell axons are also remarkably similar in these two primates (cf., Rakic and Riley, 1983; Provis et al., 1986). Using the gestational age at which retinal axon number peaks in the two species as a time standard (E90 in rhesus and E110 in human), we estimate that the putative period of neuron loss in the human lateral geniculate should extend from E60 to E120. Gestation is 165 days in rhesus monkeys and 265 days in humans.

Footnote 3. A template of geniculocortical topography could conceivably be established between geniculate axons and cells in the subplate before the geniculate axons grow into the cortex. If this is the case then the subplate may play a role in organizing or filtering axons destined for visual cortex.





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